Colony Stimulating Factor-1 (CSF-1) is the primary regulator of the survival, proliferation and differentiationof mononuclear phagocytes, including tissue macrophages and osteoclasts that play critical trophic and scavenger roles in the development and function of tissues. Recently, CSF-1 and host macrophages have been shown to enhance the development of tumor metastasis in a transgenic mouse mammary carcinoma model and host CSF-1 antisense oligonucleotides have been shown to suppress late-stage tumor growth in a human malignant embryonic tumor xenograft model. Thus, host CSF-1 production plays an important role in the later stages of tumor growth and in tumor metastasis and angiogenesis. CSF-1 is normally secreted as a gtycoprotein or proteoglycan, both of which are found in the circulation, and expressed at the cell surface as a biologically active, membrane-spanning glycoprotein. We have developed transgenic mice that express, in a normal fashion, only one of each of these forms and preliminary analysis indicates that these 3 forms of CSF-1 have different functions. The effects of all 3 forms of CSF-1 are mediated via the CSF-1 receptor (CSF-1R), an ~165-kDa tyrosine kinase encoded by the c-fms protooncogene. The phosphorylation of particular tyrosine residues in the cytoplasmic domain of the CSF-1 R is important for the activation of specific signaling pathways. The overall aim of this proposal is to identify and test, as therapeutic targets, elements of CSF-1 signaling that are critical for the metastasis-enhancing effects of CSF-1 in mammary carcinoma. The specific aims are: 1. To analyse the role of the three known forms of CSF-1 in mouse mammary carcinoma metastasis. 2. To identify CSF-1R phosphotyrosine-regulated signaling pathways that enhance metastasis and determine how they regulate macrophage adhesion, motility, invasion and gene expression. 3. To utilize CSF-1 antisense oligonucleotide and CSF-1R antibody treatment to inhibit metastasis and investigate regulation of the tumor microenvironment by CSF-1 intravitally. The proposed studies will utilize transgenic mouse mammary tumor models in which it is also proposed to directly visualize tumor cells and macrophages intravitally.